Chitosan (CS), a polysaccharide consisting of β-(1,4)-linked glucosamine units, has been extensively investigated for developing hydrogels with unique properties It is known that CS is extracted from fungal cell walls and exoskeletons of arthropods such as crabs, shrimp and krill. It holds several characteristics desirable for biomedical applications, such as: biocompatibility, biodegradation, bioadhesivity, anti-bacterial effects and no toxicity.
In recent years, injectable in situ forming hydrogels are receiving considerable attention for a variety of biomedical applications such as sustained drug delivery, cell encapsulation and scaffolds for tissue engineering (Tae et al., Biomaterials, 26, 5259-5266, 2005). Medical hydrogel has a great advantage including conventional implantation surgery, easy handling by clinic personnel, reducing pain, less complications, reduced healing period, minimal scarring, reduced surgery time, and the ability to conform to irregular defects. Several requirements need to be met for an ideal medical hydrogel, which include: (1) a sol-to-gel transition before and after injection into the sites of injury, (2) a biodegradable or gradually dissolving character, (3) both the hydrogel and the degradation products should be biocompatible, and (4) the gel should present desirable properties for the intended application, for instance, sustained release profile for drug delivery systems, or cell adhesive capabilities for tissue engineering. Recent publications on medical hydrogels highlighted various types of in vivo forming hydrogels, which included thermo-sensitive, pH-sensitive, photo-crosslinked, stereocomplexed, and peptide-based hydrogels. Given the good properties of the CS, hydrogels based on CS were found to be excellent candidates for a variety of medical and pharmaceutical applications (Berger et al., Eur. J. Pharm. Bio. Pharm., 57: 19-34, 2004). Recently, thermo-sensitive hydrogels have received much attention as they can keep liquid form at room temperature but form the hydrogel at body temperature under physiological condition (Cheng et al., Biomaterials, 32: 6953-6961, 2011).
A thermally-responsive composite hydrogel has been developed and synthesized by Bush, which is a chitosan and xylan composite thereto-gelling solution to allow regulating the conditions in which the chitosan and xylan solution will gel. (Bush, U.S. Pat. No. 8,623,403).
It has been proved to use gels for the treatment of diseases of the mucous membranes such as nasal, oral, pharyngeal and urogenital regions, particularly hydrogels, which can be used for protecting mucous membranes as well as for keeping them moist.
However, known gels adhere poorly to the mucous membrane, and cannot maintain them for a sufficient long time in the location to be treated. Further, there is a long-existing problem in the treatment of the diseases in eyes, particularly the therapeutic agent that should be applied to cornea and conjunctiva of an eye. For a pharmaceutical composition for the disease in eyes, it is desirable to last as long as possible in order to keep the eye moist, and to allow the therapeutic agent to act locally. In addition, for a pharmaceutical composition for topical administration in eyes, highly viscous gels should be used but they would pearl off from the mucous membrane of the eyes so that the desired action cannot be achieved.
Consequently, it is still desirable to develop new formulations with better properties for various medical applications, particularly for a delivery through mucous membrane in a subject.